Pulmonary Hypertension [PH] covers a variety of conditions that result in abnormally high blood pressure in the lungs. PH can be in the form of pulmonary arterial hypertension (PAH) occurring in either its idiopathic (IPAH) or hereditary (hPAH) and also in association with other diseases (APAH) e.g. connective tissue disease. PH can also result from left heart disease, lung diseases (particularly Congestive Obstructive Disease [COPD] and pulmonary fibrosis), thrombo-embolism as well as may other multifactorial conditions such as portal hypertension, sickle cell disease and HIV. The prognosis for patients suffering from PH is poor and varies between disease groups. Current management of the disease includes the use of calcium channel blockers, diuretics, enthothelin receptor antagonists, prostacyclins, soluble guanalate cyclase and phosphodiesterase inhibitors. The side effect profiles of these treatments can result in further reduced quality of life and unsatisfactory disease control. In lung transplantation is the only curative treatment but is very rarely done. Therefore there is a continuing need to identify new treatments and agents that are effective at slowing progression and/or reversing PH and which do not have the problems associated with current treatments.
Osteoprotegerin (OPG) is a protein of the Tumour Necrosis Factor (TNF) receptor family and binds at least two ligands; TNF-related apoptosis inducing ligand [TRAIL] which is a TNF-like cell surface molecule involved in the induction of apoptosis in cancer cells and Receptor activator of NFkB ligand [RANKL] which is expressed on osteoclast precursors, dendritic cells, T-cells and haematopoietic precursors. OPG is seen as one of a number of decoy receptors for TRAIL, acting to modulate its ability to target cancer cells. OPG might be expected to enhance cancer cell survival if present at a relevant site and its ability to increase the survival of tumour cells has been documented. RANKL interacts with RANK on cell surfaces to stimulate the production and activity of osteoclasts, the principal cells involved in bone turnover. The interaction of OPG with RANKL inhibits RANKL's ability to bind to RANK and stimulate osteoclasts and it is this activity of OPG that confers its ability to reduce bone loss.
The activity of OPG in bone metabolism is well known in the art. U.S. Pat. No. 6,015,938 discloses a transgenic non-human animal that expresses OPG and its use in analysing the involvement of OPG in bone metabolism. U.S. Pat. No. 6,284,740 discloses a gene therapy method for increasing the amount of OPG produced by a mammal thereby increasing bone density. U.S. Pat. Nos. 6,284,728 and 6,613,544 disclose and claims an OPG polypeptide and a nucleic acid molecule that encodes OPG respectively. U.S. Pat. No. 6,316,408 discloses a method to treat or prevent a bone disease by administration of an osteoclast activation and differentiation factor Transgenic mice lacking expression of OPG are described in U.S. Pat. No. 6,087,555. In all cases OPG and its involvement in bone metabolism is taught. In none of the prior art cited is the involvement of OPG in PH suggested or the beneficial effects of blocking OPG activity and its therapeutic effect on PH development.
This disclosure relates to the use of OPG antagonists in the treatment of PH. We illustrate this using antagonistic antibodies directed to OPG and show that blocking OPG activity protects animals that have a predisposition to PH and the reversal of pathological symptoms.